Background

Diffuse parenchymal lung diseases (DPLDs) comprise a heterogenous group of disorders. Clinical, physiologic, radiographic, and pathologic presentations of patients with these disorders are varied (an example is shown in the image below). However, a number of common features justify their inclusion in a single disease category.

Some of these disorders, for example, RBILD, DIP, and PLCH, are clearly associated with smoking. Some forms of DPLD, as noted above, may also be related to occupational, environmental, drug, radiation exposure, or systemic illness such as collagen-vascular disease. This article presents a broad overview, with an emphasis on those etiologies that result in pulmonary fibrosis not discussed elsewhere in this series.

Pathophysiology

A common pathophysiology has been postulated for these disorders. It is thought to begin with acute injury to the pulmonary parenchyma, leading to chronic interstitial inflammation, then to fibroblast activation and proliferation, and finally progressing to the common endpoint of pulmonary fibrosis and tissue destruction. Current research indicates that inflammation is less important in IPF, which appears to be primarily a disorder of fibroblast activation and proliferation in response to some as yet unknown trigger(s).

The DPLDs typically manifest with the insidious onset of respiratory symptomatology, although onset can be acute and rapidly progressive, as in COP or AIP.

Pathologically, all DPLDs manifest histologically with disease largely within the interstitial compartment of the lung. However, alveolar and airway architecture also may be disrupted to varying degrees. The histologic patterns of UIP, DIP, nonspecific interstitial pneumonitis (NSIP), HSP, LIP, COP, giant cell pneumonitis, and granulomatous pneumonitis are most common and are focused in the alveolar, lobular, and lobar septa, impacting alveoli, small airways, and pulmonary vasculature.

Epidemiology

Frequency

United States

As a group, diffuse interstitial diseases of the lung are uncommon. Based on the Bernalillo County, NM, USA registry data published in 1994, the overall estimated incidence is approximately 30 cases per 100,000 persons per year[1] . Rates of interstitial lung disease are somewhat higher in men than in women, and the epidemiology is markedly affected by age and occupational exposures. Of patients referred to a pulmonary disease specialist, an estimated 10-15% have a DPLD.

International

Although little published data exist comparing worldwide prevalence, significant differences are apparent. The Bernalillo County study estimated a prevalence of 80.9 cases per 100,000 population in men and 67.2 cases per 100,000 population in women. In comparison, a Japanese study estimated a prevalence of 4.1 cases per 100,000 population; a study in the Czech Republic reported 7-12 cases per 100,000 population; and data from a Finnish registry indicated 16-18 cases per 100,000 population.

Mortality/Morbidity

The natural history of diffuse interstitial lung diseases varies among different diagnostic entities and among individuals with the same diagnosis.

Some diseases are insidious in onset and gradual but unrelenting in progression (eg, similar to IPF), while other diseases are acute in onset but responsive to therapy (eg, COP).

Diseases that most closely approximate IPF have a similar mortality rate of approximately 50% at 5 years.

In the United States, mortality attributed to all types of DPLDs is estimated to be 10-15% of that of chronic obstructive pulmonary disease (COPD).

Race

Diffuse interstitial diseases of the lung sometimes show racial predilections. Examples include sarcoidosis, which is more common in those of African ancestry in the United States. In contrast, PLCH, also known as histiocytosis X, primarily affects Caucasians.

Sex

Several diffuse interstitial diseases of the lung show sexual predilections. IPF affects men more than women (at a ratio of 1.5:1), while LAM and pulmonary tuberous sclerosis exclusively affect women.

The Bernalillo County study estimated an incidence of 31.5 cases per 100,000/year in men and 26.1 cases per 100,000/year in women.

Women are much more likely to develop rheumatologic/connective-tissue disease than men and thus are more likely to experience pulmonary manifestations of those diseases. However, when affected, men with certain rheumatologic diseases (eg, rheumatoid arthritis) are more likely to develop pulmonary manifestations than women.

The pneumoconioses (eg, silicosis) are much more common in men than in women, probably because of higher rates of occupational exposure.

Age

Many of the DPLDs develop over many years and therefore are more prevalent in older adults. For example, most patients with IPF present in the sixth or greater decade of life. Others forms of interstitial lung disease, such as sarcoidosis, LAM, connective-tissue disease–associated lung disease, and inherited forms of lung disease primarily present in younger adults.

History

The clinical history offered by patients with a DPLD is variable and related to the underlying disease process. Many patients with DPLD, particularly IPF/UIP, may experience acute exacerbations of the disease with subsequent persistent decrement in lung function, which has become increasingly recognized.

In general, all manifest primarily with respiratory symptoms that may be erroneously attributed to aging, obesity, deconditioning, or recent respiratory tract infection.

Dyspnea is the most frequent symptom, but chronic cough, wheezing, hemoptysis, and chest pain can occur.

Digital clubbing is common with some diagnoses (eg, IPF and asbestosis) and may first be noted by the patient. When it develops in a patient with known interstitial lung disease, it is usually indicative of advanced fibrosis. However, it may also herald an underlying bronchogenic carcinoma.

Clinical history may include the following:

Incidental diagnosis may be made from a chest radiograph or abnormal screening spirometry findings obtained for unrelated reasons.

Diagnosis may occur as a result of screening for high-risk occupational exposure, such as asbestos.

Medical attention may be sought for other manifestations of systemic illness that also affect the lungs.

Broadly, the manifestations of fibrotic lung disease can be grouped as follows:

They may be chronic, insidious, and slowly progressive.

They may be subacute, with a resolving, remitting, relapsing, or progressive course.

They may be acute, with a fulminant, progressive, remitting, or resolving course.

Disorders with chronic, insidious, and slowly progressive courses are those that clinically resemble IPF and usually share a common pathology (ie, UIP).

Development of clinically apparent lung diseases related to occupational exposures (eg, pneumoconiosis) generally occurs many years after the exposure. Radiation fibrosis often develops months to years after radiation exposure.

A lag time of months or years can occur between the use of pulmonary toxic medications and the development of fibrotic disease. The effect can be dose-dependent (eg, bleomycin), although, in other cases, the relationship is less clear.

Pulmonary manifestations of rheumatologic/connective-tissue disease may develop in advance of, coincident with, or many years after the onset of articular disease.

Pulmonary sarcoidosis, although sometimes acute or subacute in onset, in some cases may present insidiously over time.

Subacute presentations with a variable course are typified by COP.

COP often develops weeks or months after the onset of a flulike illness.

Patients can present to medical attention with dyspnea or exercise intolerance.

The course is variable and may either spontaneously remit or progress.

The disorder is thought to be very responsive to steroid therapy, although it may recur when steroids are withdrawn or tapered.

In some cases, COP may progress to end-stage fibrotic lung disease.

Disorders with an acute onset are typified by AIP, which is an idiopathic form of severe lung injury.

The histopathology is that of adult respiratory distress syndrome with diffuse alveolar damage.

Patients present either with no antecedent history of lung disease or as part of an accelerated phase of underlying interstitial disease.

Most patients progress rapidly to respiratory failure.

Some patients may improve with steroids or other immunosuppressive therapy.

Physical

Varied etiologies make generalization of physical examination findings difficult for patients with DPLD. However, clinical examination findings noted in patients with idiopathic pulmonary fibrosis are frequently noted in patients with other DPLDs.

Patients frequently are dyspneic, which may be more pronounced with activity and generally is associated with an accompanying tachypnea.

Central cyanosis may be present if significant hypoxemia and arterial oxygen desaturation are present.

Fine end-inspiratory pulmonary rales (Velcro rales) are a common finding and may be difficult to distinguish from those auscultated in patients with congestive heart failure. Pulmonary sarcoidosis and other granulomatous disorders are often an exception.

Wheezes may be heard and reflect airway involvement, as in sarcoidosis.

A pulmonary squawk has been described with HSP.

A right-sided gallop (S3), an accentuated second heart sound (P2) with fixed or paradoxic splitting, and a right ventricular lift may be present. These indicate the presence of cor pulmonale.

Digital clubbing may accompany many of these disorders, as previously discussed.

Disease-specific findings include the following:

Generalized lymphadenopathy often occurs with sarcoidosis.

Cutaneous and articular findings are associated with rheumatologic disease.

Laboratory Studies

Routine blood analysis and serum chemistries are of limited value, and findings generally are nonspecific.

Serologic testing for rheumatologic disease or vasculitis (eg, antinuclear antibodies, rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, anticitrulline antibody, antineutrophil cytoplasmic antibodies, antiglomerular basement membrane) may be appropriate in specific cases, as may serum precipitins for common hypersensitivity antigens. ACE testing is not very specific or sensitive but may offer a confirmatory clue to the diagnosis of sarcoidosis.

Honeycombing is a late finding and correlates with severe histopathologic findings.[2]

Findings may be normal in 10% of patients with histologically proven disease. Therefore, a complete evaluation including pulmonary function testing and, in some cases, pulmonary exercise testing, should be undertaken in all patients clinically suspected to have underlying interstitial lung disease.

Certain patterns and distributions of abnormality are suggestive of particular diseases.

IPF, asbestosis, and connective-tissue disease–related changes are most often basilar and peripheral in distribution.

Radiation fibrosis is restricted to the previous radiation port but also may have upper lung zone predominance, as may sarcoidosis, PLCH, HSP, pneumoconioses, and drug-related DPLD due to gold or nitrofurantoin therapy.

Some patterns of abnormality, such as reverse congestive heart failure or a bat-wing pattern, are described with eosinophilic pneumonia.

High-resolution chest CT scanning is more sensitive than chest radiography and may reveal characteristic, if not diagnostic, findings (see image below).[3, 4]

Procedures

Bronchiolar lavage findings are frequently abnormal although generally not diagnostic. Bronchiolar lavage is useful in evaluating the possibility of infection or malignancy. It can also be diagnostic for eosinophilic pneumonia.[5]

Transbronchial and endobronchial lung biopsies may be diagnostic, particularly for sarcoidosis or lymphangitic spread of carcinoma but frequently are not useful for other diagnoses. This is due to the patchy distribution of the majority of these diseases.

Many patients require open or thoracoscopic lung biopsy to establish a definitive diagnosis. Currently, video-assisted thoracoscopic lung biopsy is the preferred method.

The role of lung biopsy in the setting of high-resolution CT scan findings characteristic of specific disease entities remains controversial, with expert opinion weighing in on both sides.[3, 4, 6] Consensus appears to be building on the side of forgoing biopsy when the typical clinical and high-resolution CT scan features of UIP/IPF are present.

Histologic Findings

The histopathology observed in diffuse interstitial diseases of the lung is varied. The histopathologic classification of idiopathic interstitial pneumonias were updated by Katzenstein and Myers[7] in 1998 to include the following 4 subgroups: UIP, AIP (diffuse alveolar damage), DIP/RBILD, and NSIP. Different histopathologic patterns may also be found in biopsy samples from different regions of the lung in these patients, particularly those with NSIP. Sometimes interstitial lung diseases with known etiologies may manifest one of the preceding histopathologic patterns. In addition, other pathologic patterns may be found. These may be consistent with COP, granulomatous lung disease, HSP, giant cell pneumonitis (hard-metal pneumoconiosis), eosinophilic pneumonia, and LIP (lymphoproliferative disorder).

Interpretation of histopathologic findings may be difficult, even in experienced hands, and disagreement may occur even among expert pathologists.[8] In 2005, a 52% rate of disagreement between local general pathologists and "expert" pathologists was documented in a retrospective analysis.[9]

Staging

Pulmonary function studies and the 6-minute walk study have demonstrated prognostic utility in IPF with histopathologic findings of UIP and NSIP. A diminished diffusion capacity (DLCO) on initial evaluation is a poor prognostic indicator, regardless of histologic type. Egan et al[10] have proposed a classification scheme of advanced versus limited disease based on a cutoff value of DLCO greater or less than 40%. Similarly, a trough saturation of less than 88% during a 6-minute walk study has been shown to confer a worse prognosis. Serial decrements in functional vital capacity and DLCO over time are also associated with increased mortality.

Medical Care

Treatment is best determined by the specific diagnosis. Unfortunately, a specific etiology often is not determined. General supportive measures include the following:

Smoking cessation should be counseled.

Good pulmonary hygiene is important.

Supplemental oxygen therapy may be useful for any patients who demonstrate significant hypoxemia (oxygen saturation [SaO2] less than or equal to 88% or PaO2 < 55 mm Hg while breathing room air either at rest or upon exertion).

If inhalational exposures are thought to be the etiology, as in HP and occupational forms of interstitial lung disease, removal from exposure is mandatory.

If a toxic medication is suspected, its discontinuation is mandated.

Respiratory infections should be promptly treated.

Pulmonary rehabilitation may improve exercise tolerance and quality of life.

Other immunosuppressive or antifibrotic agents such as colchicine, cyclosporine, and D-penicillamine may have a role in specific cases. Empiric use of these medications without a specific diagnosis should be discouraged because they have significant toxicities.

Interferon-gamma-1b,[11] pirfenidone,[12] and N-acetylcysteine[13] have been studied for the treatment of IPF. Interferon-gamma-1b initially appeared to have a favorable effect. This, however, was not supported in a larger follow-up study. Some evidence suggests that pirfenidone and acetylcysteine may have some benefit in IPF. Further investigation is still needed, particularly in other forms of DPLD. As much remains unknown regarding the optimal therapy for DPLD, eligible patients may benefit from enrollment in an experimental trial.

A 2008 multisystem, randomized, controlled study of bosentan, an endothelin-1 receptor antagonist, and potentially anti-fibrotic agent, did not show superiority over placebo. However, a trend toward delay in progression of disease and improvement in mortality was noted, which was more pronounced in patients with UIP documented by surgical biopsy.[14] Additional phase III trials are ongoing.

Other novel potential therapeutic agents, such as recombinant TNF-alpha antagonists and tyrosine kinase inhibitors, are currently under investigation. These agents are further described in a recently published comprehensive review.[15]

Surgical Care

Surgery in the form of either thoracoscopic (preferred) or open lung biopsy is often indicated to obtain tissue specimens for definitive diagnosis.

More recently, lung transplantation has become a treatment option for selected patients with advanced disease refractory to medical therapy.[16] It is the only interventional modality that has been shown to increase survival time in patients with UIP/IPF.[17, 18]

Survival rates worldwide after single lung transplantation are approximately 74% at 1 year, 58% at 3 years, 47% at 5 years, and 24% at 10 years.

Survival rates are lower for bilateral lung transplantation.

Following transplantation, patients overall report improved quality of life with better physical, social, and general health functioning.

Medication Summary

Medications are best used for specific diagnoses. However, corticosteroids, cytotoxic agents, and, more recently, antifibrotics, antioxidants, and other immunosuppressive agents have been used with varying success in some forms of DPLD.

In general, NSIP, DIP, and COP have been found to be more responsive to corticosteroids and immunosuppressive therapies. UIP is generally thought to be unresponsive to these modalities, and thus, additional research in the form of clinical trials evaluating potentially promising agents continues. RBILD responds to smoking cessation.

Cyclophosphamide (Cytoxan, Neosar)

Clinical Context:
Chemically related to nitrogen mustards. As an alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells of immune system. Possibly a steroid-sparing medication.

Azathioprine (Imuran)

Clinical Context:
Inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting synthesis of DNA, RNA, and proteins. These effects may decrease proliferation of immune cells and result in lower autoimmune activity. Possibly a steroid-sparing medication.